Methamphetamine (METH) use can result in the development of repetitive behaviors that may be related to enhanced gene expression in the neurons of the rostral patch compartment of dorsal striatum, relative to the surrounding rostral matrix compartment. Mu opioid receptors are densely expressed on the neurons of the patch compartment, and their activation may contribute to METH-induced changes in gene expression within the patch compartment. We posit that during METH use, endogenous mu opioid receptor ligands are released into the dorsal striatum where they activate mu opioid receptors on the neurons of the rostral patch compartment and increase gene expression within the patch compartment, resulting in changes in behavior. The goal of this application is to determine the role of mu opioid receptor activation on METH-induced changes in gene expression in the rostral patch compartment of dorsal striatum and behavior. Specific Aim I will examine the effects of an intrastriatally infused mu opioid receptor antagonist on METH-induced gene expression in the rostral patch and matrix compartments and behavior. Specific Aim II will involve examination of the effects of an intrastriatally infused mu opioid receptor agonist on METH-induced gene expression in the rostral patch and matrix compartments and behavior. In the long term, the data from these studies will provide the basis for further elucidation of the functional differences between the patch and matrix compartments of dorsal striatum and their roles in the expression of repetitive behaviors. The information generated from this proposal may also aid in developing potential therapeutic interventions for treating the untoward neurochemical and behavioral effects of METH use. One of the undesirable effects of psychostimulant use is the development of uncontrollable, repetitive behaviors, which are the result of changes in the expression of certain genes within the brain. These changes in gene expression the brain are also thought to lay the foundation for addiction. The release of peptides (small proteins) in the brain may contribute to these changes in gene expression in the brain and subsequent behaviors. Information from this proposal could be used to develop anti-peptide compounds for the treatment of psychostimulant abuse and addiction.